Skip to main content

Advertisement

SpringerLink
Log in

Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk non-BRCA1/2 French Canadian breast cancer families

  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Cowden syndrome is a disease associated with an increase in breast cancer susceptibility. Alleles in PTEN and other breast cancer susceptibility genes would be responsible for ∼25% of the familial component of breast cancer risk, BRCA1 and BRCA2 being the two major genes responsible for this inherited risk. In order to evaluate the proportion of high-risk French Canadian non-BRCA1/BRCA2 breast/ovarian cancer families potentially harboring a PTEN germline mutation, the whole coding and flanking intronic sequences were analyzed in a series of 98 breast cancer cases. Although no germline mutation has been identified in the coding region, our study led to the identification of four intronic variants. Further investigations were performed to analyze the effect of these variants, alone and/or in combination, on splicing and PTEN protein levels. Despite suggestive evidence emerging from in silico analyses, the presence of these intronic variants do not seem to alter RNA splicing or PTEN protein levels. In addition, as loss of PTEN or part of it has been reported, Western blot analysis has also been performed. No major deletion could be identified in our cohort. Therefore, assuming a Poisson distribution for the frequency of deleterious mutation in our cohort, if the frequency of such deleterious mutation was 2%, we would have had a 90% or greater chance of observing at least one such mutation. These results suggest that PTEN germline mutations are rare and are unlikely to account for a significant proportion of familial breast cancer cases in the French Canadian population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

BRRS:

Bannayan-Riley-Ruvalcaba syndrome

CD:

Cowden disease

Dr :

Dario rerio

EBV:

Epstein-Barr virus

EST:

Expressed sequence tag

Gg :

Gallus gallus

Hs :

Homo sapiens

MAF:

Minor allele frequency

Md :

Monodelphis domestica

Mm :

Mus musculus

PDZ:

PSD-95/Dlg/ZO-1 domain

PEST:

Proline, glutamic acid, serine, and threonine domain

Pt :

Pan troglodytes

RPA:

Ribonuclease protection assay

Tr :

Takifugu rubripes

WT:

Wild type

References

  1. Collaborative Group on Hormonal Factors in Breast Cancer (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358(9291):1389–1399

    Article  Google Scholar 

  2. Ford D, Easton DF, Stratton M et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62(3):676–689

    Article  PubMed  CAS  Google Scholar 

  3. Antoniou A, Pharoah PD, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130

    Article  PubMed  CAS  Google Scholar 

  4. CHEK2 Breast Cancer Case-Control Consortium (2004) CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet. 74(6):1175–1182

    Article  Google Scholar 

  5. Seal S, Thompson D, Renwick A et al (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38(11):1239–1241

    Article  PubMed  CAS  Google Scholar 

  6. Ball S, Arolker M, Purushotham AD (2001) Breast cancer, Cowden disease and PTEN-MATCHS syndrome. Eur J Surg Oncol 27(6):604–606

    Article  PubMed  CAS  Google Scholar 

  7. Lynch ED, Ostermeyer EA, Lee MK et al (1997) Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet 61(6):1254–1260

    Article  PubMed  CAS  Google Scholar 

  8. Mercapide J, Zhang SY, Fan X et al (2002) CCND1- and ERBB2-gene deregulation and PTEN mutation analyses in invasive lobular carcinoma of the breast. Mol Carcinog 35(1):6–12

    Article  PubMed  CAS  Google Scholar 

  9. Figer A, Kaplan A, Frydman M et al (2002) Germline mutations in the PTEN gene in Israeli patients with Bannayan-Riley-Ruvalcaba syndrome and women with familial breast cancer. Clin Genet 62(4):298–302

    Article  PubMed  CAS  Google Scholar 

  10. Kurose K, Gilley K, Matsumoto S et al (2002) Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 32(3):355–357

    Article  PubMed  CAS  Google Scholar 

  11. Shugart YY, Cour C, Renard H et al (1999) Linkage analysis of 56 multiplex families excludes the Cowden disease gene PTEN as a major contributor to familial breast cancer. J Med Genet 36(9):720–721

    PubMed  CAS  Google Scholar 

  12. Haiman CA, Stram DO, Cheng I et al (2006) Common genetic variation at PTEN and risk of sporadic breast and prostate cancer. Cancer Epidemiol Biomarkers Prev 15(5):1021–1025

    Article  PubMed  CAS  Google Scholar 

  13. Carroll BT, Couch FJ, Rebbeck TR et al (1999) Polymorphisms in PTEN in breast cancer families. J Med Genet 36(2):94–96. Erratum in: J Med Genet 2000, 37(7):559

  14. Durocher F, Guénard F, Desjardins S et al (2005) Inherited susceptibility to breast cancer: accomplishments and challenges. In: Sinnett D (eds) Molecular genetics of cancer. Research Signpost, Kerala

  15. Simard J, Dumont M, Moisan AM et al (2007) Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multi-step testing approach in French-Canadian high-risk breast and ovarian cancer families. J Med Genet 44(2):107–121

    Google Scholar 

  16. Vezina H, Durocher F, Dumont M et al (2005) Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families. Hum Genet 117(2–3):119–132

    Article  PubMed  CAS  Google Scholar 

  17. Durocher F, Labrie Y, Soucy P et al (2006) Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian Breast/Ovarian Cancer Families. BMC Cancer 6:230

    Article  PubMed  CAS  Google Scholar 

  18. Rhei E, Kang L, Bogomolniy F et al (1997) Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res 57(17):3657–3659

    PubMed  CAS  Google Scholar 

  19. Teng DH, Hu R, Lin H et al (1997) MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57(23):5221–5225

    PubMed  CAS  Google Scholar 

  20. Weng LP, Smith WM, Dahia PL et al (1999) PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. Cancer Res 59(22):5808–5814

    PubMed  CAS  Google Scholar 

  21. Chenna R, Sugawara H, Koike T et al (2003) Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res 31(13):3497–3500

    Article  PubMed  CAS  Google Scholar 

  22. Pertea M, Lin X, Salzberg SL (2001) GeneSplicer: a new computational method for splice site prediction. Nucleic Acids Res 29(5):1185–1190

    Article  PubMed  CAS  Google Scholar 

  23. Shapiro MB, Senapathy P (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15(17):7155–7174

    Article  PubMed  CAS  Google Scholar 

  24. Senapathy P, Shapiro MB, Harris NL (1990) Splice junctions, branch point sites, and exons: sequence statistics, identification, and applications to genome project. Methods Enzymol 183:252–278

    Article  PubMed  CAS  Google Scholar 

  25. Reese MG, Eeckman FH, Kulp D et al (1997) Improved splice site detection in Genie. J Comput Biol 4(3):311–323

    Article  PubMed  CAS  Google Scholar 

  26. Pagani F, Baralle FE (2004) Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5(5):389–396

    Article  PubMed  CAS  Google Scholar 

  27. Lim LP, Burge CB (2001) A computational analysis of sequence features involved in recognition of short introns. Proc Natl Acad Sci USA 98(20):11193–11198

    Article  PubMed  CAS  Google Scholar 

  28. Perren A, Weng LP, Boag AH et al (1999) Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol 155(4):1253–1260

    PubMed  CAS  Google Scholar 

  29. Depowski PL, Rosenthal SI, Ross JS (2001) Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol 14(7):672–676

    Article  PubMed  CAS  Google Scholar 

  30. Bose S, Wang SI, Terry MB et al (1998) Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene 17(1):123–127

    Article  PubMed  CAS  Google Scholar 

  31. Chen ST, Yu SY, Tsai M et al (1999) Mutation analysis of the putative tumor suppression gene PTEN/MMAC1 in sporadic breast cancer. Breast Cancer Res Treat 55(1):85–89

    Article  PubMed  CAS  Google Scholar 

  32. Olschwang S, Serova-Sinilnikova OM, Lenoir GM et al (1998) PTEN germ-line mutations in juvenile polyposis coli. Nat Genet 18(1):12–14

    Article  PubMed  CAS  Google Scholar 

  33. Nassif NT, Lobo GP, Wu X et al (2004) PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene 23(2):617–628

    Article  PubMed  CAS  Google Scholar 

  34. Agrawal S, Pilarski R, Eng C (2005) Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN. Hum Mol Genet 14(16):2459–2468

    Article  PubMed  CAS  Google Scholar 

  35. Hamilton JA, Stewart LM, Ajayi L et al (2000) The expression profile for the tumour suppressor gene PTEN and associated polymorphic markers. Br J Cancer 82(10):1671–1676

    Article  PubMed  CAS  Google Scholar 

  36. Kong D, Suzuki A, Zou TT et al (1997) PTEN1 is frequently mutated in primary endometrial carcinomas. Nat Genet 17(2):143–144

    Article  PubMed  CAS  Google Scholar 

  37. Sakurada A, Suzuki A, Sato M et al (1997) Infrequent genetic alterations of the PTEN/MMAC1 gene in Japanese patients with primary cancers of the breast, lung, pancreas, kidney, and ovary. Jpn J Cancer Res 88(11):1025–1028

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are indebted to the participants and their families for their generosity and providing DNA samples. We would like to thank Dr Martine Dumont, Gilles Leblanc, Carolle Samson and Martine Tranchant for sample management, mutation screening, and skillful technical assistance as well as Claire Brousseau, Marie-Andrée Lajoie, Pascale Léger, Hélène Malouin and Josée Rhéaume, for genetic counselling and clinical data management at the Cancer Genomics Laboratory. We thank Anne-Marie Moisan and Lucie Larouche for MLPA analyses. A special thank to Mélanie Houde for skillful laboratory assistance. We also appreciate advice received from ethics committees. This work was supported by the Canadian Institutes of Health Research (CIHR) and Institute of Cancer and Institute of Gender and Health for the INHERIT BRCAs research program, the Fonds de la Recherche en Santé du Québec (FRSQ)/Réseau de Médecine Génétique Appliquée (RMGA), the Canadian Breast Cancer Research Alliance and the CURE Foundation. F. G. is recipient of a studentship from Fondation René Bussières, and F. D. is a recipient of a Research Career Award in the Health Sciences from CIHR/Rx&D Health Research Foundation.

Author information

Authors and Affiliations

  1. Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, CHUQ, Pavillon CHUL, Laval University, 2705 Laurier Boulevard, T2-53, Quebec City, QC, Canada, G1V 4G2

    Frédéric Guénard, Yvan Labrie, Geneviève Ouellette, Charles Joly Beauparlant & Francine Durocher

  2. Service de gynécologie, Centre Hospitalier Universitaire de Sherbrooke, Fleurimont, QC, Canada, J1H 5N4

    Paul Bessette

  3. Clinique des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Quebec City, QC, Canada, G1S 4L8

    Jocelyne Chiquette

  4. Service de médecine génétique, CHUQ, Pavillon CHUL, Quebec City, QC, Canada, G1V 4G2

    Rachel Laframboise

  5. Centre hospitalier régional de Rimouski, Rimouski, QC, Canada, G5L 5T1

    Jean Lépine

  6. Service d’hémato-oncologie, Hôpital du Sacré-Cœur, Montreal, QC, Canada, H4J 1C5

    Bernard Lespérance & Roxane Pichette

  7. Service de gynécologie, CHUQ, L’Hôtel-Dieu de Québec, Quebec, QC, Canada, G1R 2J6

    Marie Plante

Authors
  1. Frédéric Guénard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yvan Labrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geneviève Ouellette
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles Joly Beauparlant
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul Bessette
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jocelyne Chiquette
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rachel Laframboise
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean Lépine
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bernard Lespérance
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roxane Pichette
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marie Plante
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Francine Durocher
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

INHERIT BRCAs

Corresponding author

Correspondence to Francine Durocher.

Additional information

Other members of INHERIT BRCAs involved in this study are listed in Appendix 1.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10689_2007_9151_MOESM1_ESM.doc

Appendix 1

Appendix 1

Peter Bridge, Molecular Diagnostic Laboratory, Alberta Children’s Hospital, Calgary, Canada.

Yann Joly, Centre de recherche en droit public, Montreal University, Montreal, Canada.

Bartha Maria Knopper, Chaire de recherche en droit et médecine, Centre de recherche en droit public, Montreal University, Montreal, Canada.

Jacques Simard, Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, CHUQ, Pavillon CHUL and Laval University, Québec, Canada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guénard, F., Labrie, Y., Ouellette, G. et al. Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk non-BRCA1/2 French Canadian breast cancer families. Familial Cancer 6, 483–490 (2007). https://doi.org/10.1007/s10689-007-9151-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-007-9151-y

Keywords

Search

Navigation